Gene Therapies for Alzheimer’s?
Rather than using monoclonal antibody treatments like Leqembi or Kisunla to clear amyloid plaques from the brain, what if doctors could use gene therapies for Alzheimer’s to prevent the abnormal proteins from forming in the first place?
Scientists are developing gene therapies to target diseases at the genetic level. Some treatments are already approved in the U.S. for treating melanoma and spinal muscular atrophy. These therapies work by rewriting parts of the DNA: replacing harmful genes, “silencing” certain genes, or introducing new genetic material that has a positive effect.
When it comes to Alzheimer’s disease, the root cause is still unknown, but it’s clear that genes play an important role. Some, like the genetic variant APOE4, can increase Alzheimer’s risk substantially and lead to more amyloid plaque buildup in the brain.
A few gene therapies are already in clinical trials for Alzheimer’s disease, and more are likely on the way.
Editing genes to protect the brain
A specific version of the APOE gene is one of the strongest genetic risk factors for developing Alzheimer’s. People inherit one version of this gene from each parent: APOE3 doesn’t increase the risk of the disease, while APOE2 is protective. However, people who inherit one or two copies of the variant APOE4 have a much higher chance of developing the disease as compared to 10 to 20 percent for people without two copies. Meanwhile, another version of this gene, APOE2, appears to actually protect against Alzheimer’s disease.
Lexeo Therapeutics is testing a gene therapy called LX1001 for people with two copies of APOE4. The therapy is designed to deliver a copy of APOE2 into the brain to cancel out the effects of APOE4. Lexeo is set to wrap up its combination Phase 1/Phase 2 trial by the end of the year, which means we’re likely a few years away from understanding whether the approach is safe and effective.
Silencing genes that make Alzheimer’s plaques and tangles
Biogen’s new experimental drug, BIIB080, silences the gene responsible for making tau proteins, preventing them from forming tangles in the brain. The drug is currently in a Phase 2 clinical trials—the first ‘gene silencing’ therapy for Alzheimer’s to get to this trial stage. Results from the study are expected in 2026.
Alnylam Pharmaceuticals is also developing a gene-silencing therapy that targets the gene responsible for producing amyloid. Currently, their drug candidate, ALN-APP, is also early in its journey, in Phase 1 trials.
Inserting new genes
In the last decade, researchers have developed a new tool called CRISPR/Cas9 that could make developing gene therapies easier and more precise. CRISPR/Cas9 is a set of molecular tools first discovered in bacteria that make it possible to snip out, edit, and write new genes into the DNA. In the spring of 2020, researchers using these tools snipped out amyloid-producing genes in mice. Since then, there’s been an explosion in new CRISPR research in cells and animal models, laying the groundwork for human clinical trials in the future.
While gene therapy still has a way to go before it’s ubiquitous and able to be applied to all kinds of diseases, the research being done today is the basis for future endeavors. We’re excited for the possibilities of gene therapy in the battle against Alzheimer’s disease, for helping to advance medicine for healthier lives.